Our main aim in this project is to understand how mutations across many different domains of LRRK2 cause dominantly inherited Parkinsons disease. We have been particularly looking for shared effects of multiple mutations that are found in many different functional domains of the molecule. In the current period, we have followed up on our previous observations that LRRK2 interacts with two proteins at the trans-Golgi network (TGN), Rab7L1 and GAK. Interestingly, these two proteins are in loci for risk of sporadic Parkinson's disease. We have shown that all mutations in LRRK2 promote the retention of LRRK2 at the TGN. Ongoing work is aimed at understanding the mechanistic basis of this observation. We have several candidate genes that can block or promote LRRK2-Rab7L1 complexes at the TGN and are particularly interested in whether we can establish that the same events occur at the endogenous level, which has motivated us to generate induced pluripotent stem cells (IPSC) carrying LRRK2 mutations.